Primary neuroendocrine tumours (NETs) of the gallbladder are rare. In the absence of any randomised controlled trials or prospective case series, we sought trends for clinical presentation and management based on 60 patients from published literature over the last 15 years, as well as three patients from our experience, and categorised them into various subgroups according to the WHO classification for NETs. Well-differentiated NETs have an indolent course and better prognosis. Poorly differentiated neuroendocrine carcinomas, which may be of large-cell or small-cell type and may coexist with other types of carcinoma, have a poor outcome. A variety of surgical and chemotherapeutic approaches have been adopted. Surgical excision appears to prolong life, with chemotherapy perhaps adding a marginal advantage.
- small-cell carcinoma
- large-cell carcinoma
- neuroendocrine tumour
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Neuroendocrine tumours (NETs) appear in the gastrointestinal and bronchopulmonary systems. NETs of the gallbladder are rare. Carcinoids, a subtype of NETs of the gallbladder, were first described by Joel in 1929,1 and small-cell carcinoma, another subtype, by Albores-Saavedra et al in 1981.2 Interestingly, in a review of nearly 13 715 cases of carcinoids from the SEER (Surveillance, Epidemiology and End Results) database over 50 years, only 25 (0.16%) were from the gallbladder, suggesting the rarity of this disease. A further analysis of international literature for rare carcinoid tumours suggested a mere 42 cases of gallbladder carcinoids (some cases were autopsy diagnosis), with some doubts about histological certainty.3
A 58-year-old woman presented with an 18-month history suggestive of gallstones, confirmed by an ultrasound. She underwent laparoscopic cholecystectomy. A 20×20 mm nodule was identified in the gallbladder which had the features of a large-cell NET with extensive vascular and serosal invasion, with positive staining for CD56, chromogranin, CK7 and CK20, and proliferative index >50%. A follow-up CT scan (2 months later) revealed porta hepatis lymph nodes, typical of neuroendocrine metastasis, leading to radical gallbladder bed clearance, including liver segment 4B/5 excision, common bile duct excision and lymphadenectomy up to the coeliac nodes. The coeliac and hepatic artery lymph nodes showed metastatic NETs, but the liver segments and bile duct showed no evidence of tumour invasion. The patient made an uneventful recovery and was treated with five cycles of adjuvant cisplatin and etoposide chemotherapy and is alive and well 16 months after the initial operation.
A 32-year-old woman undergoing investigations for congenital absence of one kidney had an incidental segment IV liver lesion, which, on a repeat CT scan (2 months later), had markedly increased in size with exophytic growth. This prompted resection of liver segments 4b and 5 with en bloc cholecystectomy. Histological examination showed a poorly differentiated (small-cell) neuroendocrine carcinoma of the gallbladder (20×15 mm) with invasion of the muscularis, but no direct liver invasion or vascular invasion. There was liver (114×75×70 mm) and cystic node metastasis; hence it was staged as pT2pN1pM1. Immunohistochemically, the tumour was positive for CD56, chromogranin and AE1/3, and negative for CK7 and CK20. Four months later, the patient developed further metastases within the liver and retroperitoneal nodes (suggesting the aggressive nature of the small-cell variant), for which she had palliative cisplatin and etoposide. She had a partial response and is alive 9 months after treatment.
An 85-year-old man had a moderately differentiated gastric adenocarcinoma treated 15 years ago with subtotal gastrectomy. A 2-month history of anorexia and weight loss prompted an ultrasound scan (2.8 cm gallstone and a 2 cm bilobular mass seen in the gallbladder fundus), and a subsequent CT scan (irregular gallbladder wall thickening noted) led to laparoscopic cholecystectomy. Histology of the gallbladder showed a large-cell NET (14×15 mm) with focal adenocarcinoma, vascular invasion, serosal invasion and high-grade dysplasia at the resection margins (stage pT3pNXpMX) and was positive for CD56, chromogranin and synaptophysin, with cytoplasmic and dot perinuclear positivity for pan-cytokeratin and negative for CK7, CK19 and CK20. A follow-up CT abdomen 2 months later showed multiple liver lesions, which were octreotide scan positive but metaiodobenzylguanidine (MIBG) scan negative. The patient was treated with five cycles of carboplatin and etoposide, leading to reduced tumour burden, which was further treated with lanreotide. He died 21 months after the initial diagnosis and 2 months after an ileostomy for transverse colonic obstruction secondary to peritoneal recurrence.
The clinical features of gallbladder NETs appear similar to those of the more common adenocarcinomas of the gallbladder.4–8 Cholecystitis or right hypochondrial pain is typical, and preoperative diagnosis of malignancy is rare. Peptide non-secretory gallbladder NETs are more common than secretory NETs, and may present with symptoms of either local disease or metastasis. Secretory gallbladder NETs (serotonin, histamine, prostaglandins, vasointestinal peptide) may, additionally, present with symptoms such as diarrhoea, flushing and hyperglycaemia.9 10 Pancreatic polypeptide can inhibit gallbladder contraction and may contribute to cholelithiasis, although cholelithiasis may be incidental.11 Urine 5-hydroxyindoleacetic acid may be raised in carcinoid tumours.12 Nuclear imaging studies (octreotide scintigraphy or MIBG) may be useful.12
We sought to summarise the clinical features (demographics, histological features), management (surgical and non-surgical) and follow-up data of NETs based on literature review (1992–2008) as well as from our institution’s experience. We performed a Medline search using the MeSH terms “Gallbladder Neoplasms”, “Carcinoid Tumour” and “Neuroendocrine Tumours” published in the English language. Bibliographies were hand-searched and patients were grouped according to the WHO classification for NETs13 14 arising in other organs such as lung and pancreas. This includes four categories:
well-differentiated NETs (typical carcinoid);
well-differentiated neuroendocrine carcinoma (atypical or malignant carcinoid);
poorly differentiated neuroendocrine carcinoma (high-grade carcinoma—small-cell/large-cell types)
mixed exocrine–endocrine carcinomas.
Well-differentiated NETs (typical carcinoid)
A well-differentiated NET is a low-grade epithelial tumour of monomorphous endocrine cells with mild or no atypia, forming solid nests or trabeculae, restricted to mucosa or submucosa, with prominent organoid growth pattern, “salt-and-pepper” chromatin, small nucleoli, few mitotic figures, and no necrosis.15 They are <1 cm in size with ⩽2 mitoses/10 high power field (HPF). Kimura and Nagura16 suggested that major histocompatibility complex class II antigen HLA-DR-positive capillary endothelial cells were abundant in carcinoids but sparse in neuroendocrine carcinomas, and only 27% of the cells were positive for proliferating cell nuclear antigen in carcinoids (compared with 92% in neuroendocrine carcinomas). Thirteen cases of primary gallbladder carcinoids were reported in the last 15 years, with the median age of patient at presentation (table 1) being 56 (range 28–77) years and with female preponderance (female/male ratio, 1.2:1). All except one were surgically excised by either laparoscopic or open cholecystectomy. With the advent of laparoscopic surgery, there are likely to be more incidental diagnoses of typical carcinoid of the gallbladder.
Key learning points
Neuroendocrine tumours (NETs) of the gallbladder are rare, and radical surgery is the mainstay of treatment.
Chemotherapy has a marginal effect on these tumours, and the agents of choice are cisplatin, gemcitabine and etoposide plus 5-fluorouracil.
A well-differentiated NET (typical carcinoid) has a better prognosis than, and an indolent course compared with, a poorly differentiated or mixed NET.
For carcinoids confined to the gallbladder, surveillance without adjuvant treatment is recommended, with good overall prognosis.
Solcia E, Kloppel G, Sobin LH, et al. Histologic typing of endocrine tumours. WHO international histological classification of tumours. Heidelberg: Springer Verlag, 2000.
Capella C, Heitz PU, Höfler H, et al. Revised classification of neuroendocrine tumours of the lung, pancreas and gut. Virchows Arch 1995;425:547–60.
Maitra A, Tascilar M, Hruban R, et al. Small cell carcinoma of the gallbladder: a clinicopathologic, immunohistochemical, and molecular pathology study of 12 cases. Am J Surg Pathol 2001;25:595–601.
Fujii H, Aotake T, Horiuchi T, et al. Small cell carcinoma of the gallbladder: a case report and review of 53 cases in the literature. Hepatogastroenterology 2001;48:1588–93.
Bahadur S, Shaukat A, Gibbs J, et al. Cisplatin and gemcitabine for small cell carcinoma of the gall bladder. Am J Clin Oncol 2005;28:425–6.
Well-differentiated neuroendocrine carcinomas (malignant carcinoid)
Well-differentiated neuroendocrine carcinomas (malignant carcinoids) show moderate atypia and form solid nests, trabeculae or larger, less well-defined cellular aggregates, which invade the muscularis propria or metastasise to regional lymph nodes or the liver. These tumours are usually >1 cm and may have a mitotic index >2/10HPF and Ki67 positivity of >2%.4 Distinction from typical carcinoids is made on the basis of size, site, local extension, angioinvasion, atypia, mitotic index/proliferative activity, metastasis and ectopic hormonal products in conjunction with endocrine syndromes.4 There were five case reports (table 2) of malignant carcinoids (median age of patient 53 (range 40–81) years and female preponderance (female/male ratio, 1.5:1)). Four of the five patients had metastases on initial presentation, and two patients had multiple organ metastases. Most patients had surgery but did not receive adjuvant chemotherapy.
Current research questions
A worldwide registry of neuroendocrine tumours (NETs) in general, and those of the gallbladder in particular, should be constructed to improve our understanding of NETs.
Poorly differentiated neuroendocrine carcinomas
Poorly differentiated neuroendocrine carcinomas are an epithelial tumours composed of highly atypical, small to intermediate sized tumour cells growing in the form of large ill-defined aggregates, often with necrosis and prominent angioinvasion and/or perineural invasion with high mitotic (10/10HPF) and proliferation (Ki67 >15%) index.4 Neuron-specific enolase is expressed in ∼75% of all endocrine carcinomas, followed by synaptophysin and chromogranin, and these markers may be diffusely or more focally positive in small-cell carcinomas (the more common subtype).2 17 The large-cell subtype on the other hand has features similar to large-cell lung NETs: large cells with prominent nucleoli that show an organoid growth pattern often with rosette formation and areas of necrosis.2 15 The molecular changes in small-cell carcinomas are similar to those of gallbladder adenocarcinomas, with a high frequency of mutations in p53 (75%) and p16INK4a (33%).15 17
There were 29 such cases (table 3) (median age of patient 62 (range of 25–85) years and a slight female preponderance (female/male ratio, 1.2:1)). Metastatic disease at the time of presentation was often observed, the most common sites being regional lymph nodes, liver, lung, skeleton and adrenal glands. Laparoscopic or open cholecystectomy was performed in 12 patients, extended cholecystectomy in nine, exploratory laparotomy and biopsy in two, and no surgery in six.
The large-cell subtype has a worse prognosis than the small-cell variety. Chemotherapy is more effective for the small-cell subtype.18 23 Bhutani et al18 reported treatment with cisplatin and gemcitabine, leading to a partial response for palliation of small-cell NET, but survival rarely exceeded 1 year. Somatostatin analogues have also been used with partial success.20 21 The role of radiotherapy remains undefined because of the paucity of data. Two of the cases from our institution (case 1 and 2) illustrate the salient features.
Mixed exocrine–endocrine NETs
A mixed exocrine–endocrine carcinoma is an epithelial tumour with a predominant exocrine component but with at least one-third being of endocrine nature.4 The histogenesis of mixed exocrine–endocrine carcinoma of the gallbladder may be explained by either multidirectional differentiation of a totipotent neoplastic stem cell or simultaneous origin from columnar gallbladder epithelium and metaplastic neuroendocrine/squamous epithelium,10 22 with the most common histological combination being that of adenocarcinoma and small-cell carcinoma. Median age at presentation was 68 (range 36–85) years with female preponderance (female/male ratio, 2.2:1). Of the 16 patients with this tumour, seven underwent simple cholecystectomy, eight had extended cholecystectomy, and one had a palliative procedure (table 4). Chemotherapeutic agents such as cisplatin, carboplatin and etoposide are the drugs of choice for mixed tumours of the gallbladder. A combination approach to treatment may provide reasonable survival as illustrated by our experience in case 3.
The prognosis of NET of the gallbladder, a rare disease of mainly women over the age of 50 years, depends on the histological subtype and the stage of the disease. Surgical excision is the cornerstone of treatment. Poorly differentiated tumours exhibit highly aggressive clinical behaviour with a poor prognosis, whereas well-differentiated endocrine tumours (carcinoids) exhibit slow progression and have a significantly better prognosis. An international, prospective database with some minimum and standardised reporting fields such as those described here is required to understand the disease better.59
MULTIPLE CHOICE QUESTIONS (TRUE (T)/FALSE (F); ANSWERS AFTER THE REFERENCES)
1. Clinical features of NET of the gallbladder
The most common presentation of NETs of the gallbladder is cholecystitis
Preoperative diagnosis is possible in 90% of neuroendocrine carcinoma of the gallbladder
Carcinoid syndrome is a common association of gallbladder neuroendocrine carcinoma
Pancreatic polypeptide-secreting NETs of the gallbladder are often associated with cholelithiasis
MIBG scan is a useful tool in the diagnosis of NET of the gallbladder
2. Well-differentiated NET of the gallbladder
A well-differentiated NET of the gallbladder is a low-grade tumour
A well-differentiated NET of the gallbladder is otherwise known as a typical carcinoid
The diagnostic criterion for well-differentiated NETs of the gallbladder is that they have got >5 mitotic figures per high power field
Some NETs of the gallbladder are diagnosed incidentally from laparoscopic cholecystectomy specimens
The overall prognosis of well-differentiated NETs is poor
3. Well-differentiated neuroendocrine carcinoma of the gallbladder
Well-differentiated neuroendocrine carcinoma of the gallbladder is also known as malignant carcinoid
Well-differentiated neuroendocrine carcinoma is diagnosed when >1 cm in size with <2 mitotic figures per high power field
Ki67 positivity in well-differentiated neuroendocrine carcinoma is <2%
Angioinvasion and atypia are distinguishing features of well-differentiated neuroendocrine carcinoma
Ectopic hormone production may give rise to carcinoid syndrome
4. Poorly differentiated neuroendocrine carcinoma
Poorly differentiated neuroendocrine carcinoma has features such as severe atypia, angioinvasion and perineural invasion
Neuron-specific enolase is expressed in 30% of neuroendocrine carcinoma
High mitotic index and Ki67 >15% are specific for poorly differentiated neuroendocrine carcinoma
The large-cell subtype of poorly differentiated carcinoma of the gallbladder has features similar to large-cell lung NET
Poorly differentiated neuroendocrine tumours exhibit highly aggressive clinical behaviour and have a poor prognosis
5. Mixed exocrine–endocrine NETs
The histogenesis of mixed exocrine–endocrine carcinoma of the gallbladder may be from multidirectional differentiation of a totipotent neoplastic stem cell
The histogenesis of mixed exocrine–endocrine carcinoma of the gallbladder may be from metaplastic columnar epithelium from the gallbladder
The most common histological combination for mixed NETs is adenocarcinoma and small-cell carcinoma
Cisplatin-based combination chemotherapy offers 50% survival advantage
Surgical excision is the main treatment modality for NETs of the gallbladder
We thank Dr Pauline Leonard, consultant oncologist, Basildon Hospital for help with managing the patients.
(A) F; (B) F; (C) F; (D) T; (E) T
(A) T; (B) T; (C) F; (D) T; (E) F
(A) T; (B) F; (C) F; (D) F; (E) F
(A) T; (B) F; (C) T; (D) T; (E) T
(A) T; (B) T; (C) T; (D) F; (E) T
SI and TAM contributed equally to this work.
Funding: HMK is supported by a Clinician Scientist award from the Department of Health, UK.
Competing interests: None.